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On the occasion of receiving the Pharmaceutical Society of Japan Award 2020, I explained our research activities on the total syntheses of polycyclic alkaloids as an invited review. The structure of lundurine B, which has an unstable cyclopropane fused indoline skeleton, was proved firstly by the total synthesis. I also describe the total syntheses of optically active lundurine B and rapidilectine B utilizing asymmetric desymmetrization of the spiro intermediate. We developed an intramolecular bond formation reaction between the 2-position of the furan ring to the iminium cation (furane-iminium cation cyclization) to synthesize manzamine alkaloids. The reaction was applied to the total synthesis of the core skeleton of nakadomarin A and ircinal A. A ring-closing metathesis reaction effectively applied to the synthesis of medium and large heterocyclic rings containing the cis double bond found in the structures of nakadomarin A and ircinal A. The total synthesis of schizocommunin, a metabolite of Schizophyllum commune isolated from a patient with human allergenic bronchopulmonary mycosis, was accomplished. We could correct the error in the proposed structure by total synthesis of the natural product. A part of the mechanism of cytotoxicity expression was clarified using newly synthesized shizocommunin.

The chemistry of the 3,3,3-trifluoroprop-1-enyl (TFPE) group has attractive characteristics in medicinal chemistry as a new fluorine motif. However, there are no reports on the properties of this group because it is difficult to construct molecules with it. For the convenient construction of the TFPE group, a new fluorination reagent, CF 3 CH=CHTMS (1), was developed from commercially available chemicals with easy purification processes and excellent yields. The utility of 1 as a trifluoropropenylation reagent was exhibited in several types of reaction such as the Sonogashira cross-coupling reaction. Furthermore an indometacin analogue bearing a TFPE group showed greater pharmaceutical activity than the original indometacin. This review describes the details of these research studies under three topics: 1) synthesis of 1; 2) Sonogashira cross-coupling reaction of 1 with acetylene, followed by cyclization into an indole ring; and 3) synthesis of an indometacin analogue with a TFPE group.

The combination of several aromatic rings and/or heterocycles can induce novel functions. This phenomenon is observed in porphyrin derivatives, commonly found in hemoglobin, in the active sites of P-450, etc. The ability of these structures to interact strongly with visible light accounts for today's increased interest in the development of rationally designed porphyrinoid-based optical materials. In the pharmaceutical sciences, designing near-IR materials can be a challenge due to the high transparency of near-IR light in biological samples. Phthalocyanines (Pcs) are robust organic dyes that are absorbed in visible light. A theoretical investigation of molecular orbitals of Pcs has revealed that the introduction of a phosphorus(V) atom into a macrocyclic core leads to a narrower highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap. Following these studies, we found that certain types of Pc phosphorus(V) complexes display main absorptions beyond 1000 nm. Additionally, phosphorus(V) complexes with other azaporphyrinoids have been designed and synthesized via a relatively simple procedure. These complexes showed novel optical properties which are potentially useful in the pharmaceutical and material sciences. Furthermore, we have overcome the problem of organic radicals and antiaromatic compounds, which are generally considered to be unstable, by using a combination of serendipitous synthetic methodologies and spectroscopic techniques. These novel azaporphyrin compounds are robust and free from transition metals. They are relatively easy to synthesize and also exhibit predictable properties.

The design and development of new chiral ligands to enable precise stereocontrol in a wide variety of reactions is one of the most important branches of organic synthesis. To date, the development of hybrid ligands containing both σ-donating and π-donating groups has attracted considerable attention, with unprecedented reactivities and stereoselectivities being observed. Therefore to develop efficient hybrid chiral ligands with novel structural motifs, we envisage that helicene would be a suitable π-donor efficiently to construct a helical environment around a metal center. In this context, we herein describe our recent efforts to develop a series of novel chiral [5]helicene-derived phosphine ligands (L1, with a 7,8-dihydro[5]helicene core structure, and L2, with a fully aromatic [5]helicene core structure). The prepared ligands, and in particular L1, were found highly effective in the asymmetric allylation of 1,3-diphenylallyl acetate with indoles and etherification with alcohols. Furthermore, in the asymmetric Suzuki-Miyaura coupling reaction, L2 exhibited excellent enantioselectivities. Finally, density functional theory studies were employed to propose a model that accounts for the origin of such high enantioselectivity in these reactions.

Many tryptophan-based dimeric diketopiperazine (DKP) alkaloids including WIN 64821 and ditryptophenaline, which exhibit fascinating biological activities, have been isolated from fungi. These alkaloids possess a unique architecture; therefore several total syntheses of these compounds have been accomplished via bio-inspired reactions. Despite these elegant strategies, we were convinced that a more direct bio-inspired solution for the preparation of tryptophan-based DKP alkaloids was possible because in a true biosynthesis, direct dimerization of tryptophan occurs in aqueous media without incorporation of a protecting group on the substrates. Thus we developed direct bio-inspired dimerization reactions in aqueous, acidic media, along with a novel biomimetic pathway, to provide C2-symmetric and non-symmetric dimeric compounds from commercially available amine-free tryptophan derivatives using Mn(OAc)3, VOF3, and V2O5 as one-electron oxidants. In addition, concise two-pot or three-step syntheses of the naturally occurring dimeric DKP alkaloids (+)-WIN 64821, (-)-ditryptophenaline, and (+)-naseseazine B were accomplished with total yields of 20%, 13%, and 20%, respectively. The present synthesis has several noteworthy features: 1) the tryptophan-based C2-symmetric and non-symmetric dimeric key intermediates can be prepared on a multigram scale in one step; 2) the developed oxidation reaction was carried out in aqueous, acidic solution without deactivation of the metal oxidants; 3) protection of the primary amine can be avoided by salt formation in aqueous acid; 4) for the total two-pot operation, the reaction media are environmentally friendly water and ethanol; 5) satisfactory total yields are obtained compared with previously reported syntheses.

Introduction of carbon side chain at C(3)-position of indole ring was accomplished by using Pd-catalyzed allylation and vinylation. The selective vinylation at C(3)-position of 4-bromoindole was applied to the synthesis of optically active 4-bromotryptophan derivatives, which was used as a starting material for the synthesis of several optically active ergot alkaloids, which were clavicipitic acids, chanoclavine-I, costacalvine, and 1,1-dimethylallyltryptophan (DMAT). The three-step synthesis of optically active clavicipitic acids were accomplished without using a protecting group starting from 4-bromoindole and dl-serine. Some new synthetic reactions using unprotected amino acids were developed. Those were the biomimetic synthesis of tryptophan, the bromination of free aromatic amino acids, and the Pd-catalyzed N-allylation of free amino acids with allylic alcohol in aqueous media. Unique reactivity of π-allyl palladium complex or η3-(benzyl)palladium complex in aqueous media was found through Pd-catalyzed reaction of anthranilic acid, 2-aminobenzamide, and indole with allylic alcohols or benzyl alcohols, respectively.

This review describes a synthesis of indole compounds using multifunctional synthons. The multifunctional synthons, trienes and gramines, were respectively synthesized using Pd-catalyzed tandem cyclization/cross-coupling reaction of indolylborate with vinyl bromide, and reaction of indolylcuprate with iminium chloride. As an application of the multifunctional synthons to the indole alkaloids synthesis, we accomplished the total synthesis of ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, tetrahydroellipticine, μ-alkaloid B, μ-alkaloid D, calothrixin A, calothrixin B, tubifoline, and yuehchukene. We have also developed 6π-electrocyclization of hexatrienes catalyzed by Cu(I) trifluoromethanesulfonate toluene complexe, which is unprecedented.

Tandem reactions for efficient construction of nitrogen-containing heterocycles were developed. One-pot platinum(II)-catalyzed synthesis of indoles and isoquinolines has been achieved via isocyanates, which were derived from a Hofmann-type rearrangement of 2-alkynylbenzamides and 2-alkynylbenzylamides using a hypervalent iodine reagent. As an extension of this approach, trans-2,3-dihydro-4-quinolones were synthesized via acid-catalyzed intermolecular [2+2]-cycloaddition of aldehydes and carbamates, which were formed from nucleophilic addition of alcohols to isocyanate intermediates. Direct, efficient syntheses of the benzimidazo[2,1-a]isoquinoline ring system have been achieved with 2-bromoarylaldehydes, terminal alkynes, and 1,2-phenylenediamines by a microwave-accelerated tandem process in which a Sonogashira coupling, 5-endo cyclization, oxidative aromatization, and 6-endo cyclization can be performed in a single synthetic operation.

We have had five dreams to challenge through our life. To meet our end, we needed imaginary compounds, 1-hydroxytryptophans. This review describes how we had conceived the 1-hydroxyindole hypothesis, how we created a general synthetic method for 1-hydroxyindoles after 20 years' research, and how we have developed the chemistry of 1-hydroxytryptophans with full of new findings and discoveries. During the period, we defined "the efficient synthesis" and "the ideal synthesis" consisting of originality rate (OR), intellectual property factor (IPF), and application potential factor (APF). For evaluating the originality and the efficiency of the synthetic research, these indexes are more effective than both citation index and impact factor. Taking advantage of our 1-hydroxyindole chemistry, we have achieved three "ideal syntheses" approximately with high OR, IPF, and APF values. The methods employ only conventional reagents and reaction conditions without using any protecting groups. These methods made possible to produce such intellectual properties as leads for an alpha(2)-blocker, an inhibitor of platelet aggregation, an anti-osteoporosis agent, and a promising medicine for combating desertification, changing Gobi desert to the tract with full of green plants. These would be suitable for realizing our five dreams. Chemical conversion of enmein to gibberellin A(15), four-step total synthesis of optically active ergot alkaloids, and various new reactions for the synthesis of 4-substituted indoles are also involved.

Optically active alpha,alpha-disubstituted alpha-amino acids belong to an important class of unnatural amino acids. Since the synthesis of such amino acids involves the creation of a quaternary stereocenter, methods for their synthesis have been extensively studied. We have reported that N-t-butoxycarbonyl(Boc)-N-methoxymethyl(MOM)-amino acid derivatives undergo asymmetric alpha-alkylation in up to 93% ee. Original chiral information on an amino acid is preserved in axially chiral enolate intermediates, and thus asymmetric induction is achieved without the aid of external chiral sources (i.e., memory of chirality). Recently, we have reported a new protocol for the asymmetric cyclization of amino acid derivatives, which enables straightforward synthesis of cyclic amino acids with a tetrasubstituted carbon center from the usual alpha-amino acids in up to 98% ee. Here we report the asymmetric construction of highly substituted chiral nitrogen heterocycles via intramolecular conjugate addition of chiral enolates generated from N-Boc-N-alkylylamino acid derivatives. This method is applicable to the asymmetric construction of pyrrolidine, piperidine, tetrahydroisoquinoline, and indoline derivatives with contiguous quaternary and tertiary stereocenters.

Using a unique character of the chiral palladium complexes 1 and 2, several types of novel catalytic asymmetric reactions have been developed. In contrast to the conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine compounds were activated to form chiral palladium enolates, which underwent the enantioselective Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid activating the electrophiles, formed concomitantly during the formation of the enolates, whereby the C-C bond-forming reaction was promoted. In addition, this palladium enolate chemistry was also applicable to the electrophilic asymmetric fluorination reactions, and thus various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, and oxindoles were fluorinated in a highly enantioselective manner (up to 98% ee). It is advantageous that these reactions were carried out in environmentally friendly alcoholic solvents such as ethanol, and exclusion of air and moisture is not necessary.

Mitiglinide calcium hydrate (mitiglinide, Glufast) is a new insulinotropic agent of the glinide class with rapid onset. Mitiglinide is thought to stimulate insulin secretion by closing the ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells, and its early insulin release and short duration of action would be effective in improving postprandial hyperglycemia. In studies of various cloned K(ATP) channels, mitiglinide shows a higher selectivity for the beta-cell type of SUR1/Kir6.2 than the cardiac and smooth muscle types of K(ATP) channels in comparison with glibenclamide and glimepiride. In vitro and in vivo studies demonstrated the insulinotropic effect of mitiglinide is more potent than that of nateglinide, and mitiglinide surpassed in controlling postprandial hyperglycemia in normal and diabetic animals. In clinical trials, treatment with mitiglinide provided lasting improvement of postprandial hyperglycemia in Type 2 diabetic patients and decreased the fasting plasma glucose levels and HbA(1C) values. The incidence of adverse events related to mitiglinide were nearly equivalent to placebo; in particular there was no difference with the frequency of hypoglycemia. The results from these studies indicated that mitiglinide could be expected to possess good therapeutic features of being effective in reducing postprandial glucose excursions in the early stage of Type 2 diabetes and less incidence of events suggestive of hypoglycemia.

This review describes the discovery of new reactions in the field of heterocyclic chemistry. The reactions taken as typical examples involve 1) the photochemical ring transformations of quinolines to indole rings, 2) the ring transformations of indoles to quinazoline and quinoxaline rings, 3) the ring expansion reactions of indoles to 1H-1-benzazepines, 4) the intramolecular photo[2+2]cycloaddition reactions of 2- or 3-alkenyloxy-(or amino-)cyclohex-2-en-1-ones, 5) the syntheses of the nitrogen-containing heterocycles using the cyclizations of N-alkenylcarbamoylmethyl radicals, and 6) the general syntheses of bridged azabicyclic compounds using radical translocation/cyclization reactions. Modification of the water-soluble aminating agent hydroxylamine-O-sulfonic acid to the more powerful aminating agent O-mesitylenesulfonylhydroxylamine is also described.

Synthetic study of biologically important nitrogen-containing natural products and development of new methodologies and design of leading compounds for new pharmaceuticals are described. The first total synthesis of eudistomines, manzamine C, martefragin A, cerebroside B1b, and symbioramide was accomplished and the absolute configurations of the stereogenic centers were determined. A novel methodology useful for the synthesis of alkaloids that have perhydroisoquinoline ring system such as manzamine A and B, and related alkaloids, nakadomarin A and dynemicin A, is presented. Sphingolipids, 4-stereoisomers of 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, were synthesized and antimalaria activity was investigated. Inhibition of DNA primase by sphingosine and its analogues is described. A new synthetic methodology for alkylation and reduction of imines has been developed, and the first example of a reagent-controlled enantioselective Pictet-Spengler reaction is described. Also novel and convenient methods using transition metal and rare earth metals including alkene metathesis, asymmetric Diels-Alder reaction, imino ene reaction, selective allylic halogenation, enantioselective Pictet-Spengler reaction, and enantioselective physostigmine synthesis are described.

The leaves of a tropical plant, Mitragyna speciosa Korth. (Rubiaceae), have been traditionally used as a substitute for opium. By phytochemical studies on the constituents of the plant growing in Thailand as well as in Malaysia, several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids including new natural products were isolated. The structures of these new compounds were elucidated by the modern spectroscopic methods and/or chiral-total syntheses. The chiral total synthesis of (-)-mitragynine, a major component of this plant, was achieved. Potent opioid agonistic properties of mitragynine, which acts on mu- and delta-opioid subtype receptors, and of mitragynine pseudoindoxyl, whose analgesic activity is more potent than that of morphine, were clarified in in vitro experiments. The essential structural features in mitragynine for revealing the analgesic activity were elucidated by pharmacological evaluation of the natural and synthetic mitragynine derivatives.

This review summarizes our studies on the development of new reactivities of the indole nucleus and on its application for the synthesis. These studies involve the following five main subjects: 1) The Vilsmeier-Haack reaction was applied to 1,2,3,4-tetrahydrocarbazole and its N-alkyl compounds. The conditions and the mechanisms of the formation of three kinds of products obtained from the latter compound were clarified, and among the three products, 1,9-dimethylcarbazole-3-aldehyde was found to be useful for the syntheses of olivacine and ellipticine. 2) The Fischer indole synthesis of various 2-substituted phenylhydrazones was examined in detail and it was found that the Fischer indole synthesis of 2-sulfonyloxyphenylhydrazones served a new and convenient method for the synthesis of 7-oxygenated indoles. This reaction was applied to the synthesis of eudistomidin-A. 3) The reactivities of ethyl indole-2-carboxylate for acylation and bromination were also studied, and the use of this compound as a starting material for the synthesis of 4-methoxy-beta-carbolines was successfully investigated. 4) Acylation of ethyl pyrrole-2-carboxylate was concisely studied and this reaction was applied to the syntheses of benzene ring-substituted indoles and benz[f]indoles involving eupolauramine. 5) Two kinds of method for the debenzylation of N-benzylindoles were developed using either AlCl3-benzene or methyl lithium, and they are complementary with each other.

Nineteen benzo[a]quinolizidine alkaloids (1-19) isolated so far from Alangium plants can be classified into four types (I-IV) according to their chemical structures. Studies on racemic and chiral syntheses of these I-IV-type alkaloids are reviewed with particular emphasis on the strategies and tactics for the syntheses employed by the author. It has been found that racemic syntheses of all of these types of alkaloids are possible through the "lactim ether route" or the "3-acetylpyridine route"; and chiral syntheses, through the "cincholoipon-incorporating route" or the "chiral lactim ether route". As a result of such total syntheses, the structures and absolute configurations of four II-type, two III-type, and two IV-type Alangium alkaloids have been established. Extensions of the "chiral lactim ether route" to the syntheses of the Ochrosia alkaloid (-)-ochropposinine [(-)-93g], the Neisosperma alkaloid (-)-ochromianine [(-)-97], and the Ophiorrhiza alkaloid (-)-ophiorrhizine [(-)-98] have unequivocally established the absolute stereochemistries of these three indolo[2,3-a]-quinolizidine alkaloids.

Up to now, more than two thousands indole alkaloids having structural variety have been found from the three families of Gentianales: Loganiaceae, Apocynaceae, and Rubiaceae plants. These compounds generally possess characteristic biological activities and many of them are utilized for the medicinal purpose and for the lead-compounds to develop new synthetic drugs. The author of this review has been investigated the alkaloidal constituents of the above mentioned plants native to Japan and overseas countries. Especially, a cooperative work with Thai researchers concerning the plants in Thailand was developed. On the basis of biogenetic consideration of the structures of monoterpenoid indole alkaloids, chemical bond cleavage between the C3-N4 linkage in the C/D ring of indole alkaloids was discovered. It was speculated that, either in biogenesis, the flexibility of the ring-opening compounds having ten membered ring enabled the construction of indole alkaloids having highly strained polycyclic structures. Along with this conception, the syntheses of structurally complex indole alkaloids utilizing a biomimetic procedure have been investigated. In this review, recent results on the chemical synthesis of many skeletally varied Gelsemium alkaloids (Loganiaceae plant) are mainly described.

Ethyl 1-(difluoro-1,3,5-triazinyl)-2-methylindolizine-3-carboxylate was found to be a selective fluorescence derivatization reagent for primary and secondary amines. The reagent reacted with amines in aqueous acetonitrile in the presence of sodium hydroxide to give the corresponding fluorescent products, which could be separated on a TSK gel ODS-80TM reversed-phase column with aqueous methanol as eluent. 2-Phenethylamine and spermidine were used to investigate the derivatization conditions. The detection limits (signal-to-noise ratio = 3) of each compound were 3 and 2 pmol per 10 microliters injection volume, respectively. Alcohols, thiols and aromatic amines did not give any fluorescent products under these derivatization conditions.